Selenomethionine Attenuates Sepsis-Induced Skeletal Muscle Atrophy by Inhibiting ROS/NLRP3 Signaling.

Objective: Sepsis-induced muscle atrophy (SIMA) significantly impairs patient quality of life, yet effective therapeutic strategies remain limited. This study aimed to investigate the protective effects of selenomethionine (Se-Met) on sepsis-induced skeletal muscle atrophy and explore the underlying molecular mechanisms, with the goal of providing a novel theoretical foundation and potential therapeutic approach for sepsis-associated muscle injury.

Methods: A murine sepsis model was established via cecal ligation and puncture (CLP), followed by treatment with varying doses of Se-Met. Survival rate, body weight, skeletal muscle mass, and muscle strength were evaluated. Histological analysis (HE staining) was used to assess muscle fiber cross-sectional area. Protein expression levels of Atrogin-1, MuRF1, and pyroptosis-related markers (NLRP3, Caspase-1, GSDMD, IL-18, IL-1β) were examined via Western blot. In vitro, C2C12 myoblasts were stimulated with lipopolysaccharide (LPS) and treated with Se-Met to assess oxidative stress markers (ROS, MDA, SOD, GSH-Px), pyroptosis-related proteins, and inflammatory cytokines (e.g., IL-6, IL-18). ROS scavenger NAC, NLRP3 agonist, and ROS inducer were employed in mechanistic studies to further elucidate the molecular mechanisms.

Results: Se-Met significantly improved survival, body weight, and muscle strength in septic mice, and alleviated skeletal muscle atrophy. Mechanistically, Se-Met inhibited the NLRP3/Caspase-1/GSDMD signaling axis, thereby reducing pyroptosis and the expression of inflammatory cytokines such as IL-6, IL-18, and IL-1β. Furthermore, Se-Met decreased ROS accumulation, enhanced antioxidant enzyme activities, and suppressed pyroptosis through regulation of the ROS/NLRP3 pathway, ultimately reducing protein degradation mediated by Atrogin-1 and MuRF1.

Conclusion: This study demonstrates that Se-Met mitigates sepsis-induced skeletal muscle atrophy by exerting antioxidant effects, inhibiting pyroptosis, and modulating inflammatory responses. The findings highlight the critical role of the ROS/NLRP3 signaling pathway in the protective action of Se-Met, providing new experimental evidence for its potential application in sepsis and other oxidative stress-related diseases.